6-7584884-G-C

Position:

• chr6-7584884-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_004415.4(DSP):​c.7622G>C​(p.Arg2541Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2541K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.49

Genes affected

DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-7584884-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.7622G>C	p.Arg2541Thr	missense_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.6293G>C	p.Arg2098Thr	missense_variant	24/24		NP_001305963.1
DSP	NM_001008844.3	c.5825G>C	p.Arg1942Thr	missense_variant	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.7622G>C	p.Arg2541Thr	missense_variant	24/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.5825G>C	p.Arg1942Thr	missense_variant	24/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.6293G>C	p.Arg2098Thr	missense_variant	24/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	-0.088
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	0.61	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.055	T;D
Polyphen		0.026	B;.
Vest4		0.57
MutPred		0.59		Loss of stability (P = 0.0472);.;
MVP		0.63
MPC		0.42
ClinPred		0.87	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142078450; hg19: chr6-7585117;